Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

Research output: Contribution to journalArticle

Researchers

  • Panu K. Luukkonen
  • Auli Nick
  • Maarit Hölttä-Vuori
  • Christoph Thiele
  • Elina Isokuortti
  • Susanna Lallukka-Brück
  • You Zhou
  • Antti Hakkarainen

  • Nina Lundbom
  • Markku Peltonen
  • Marju Orho-Melander
  • Matej Orešič
  • Tuulia Hyötyläinen
  • Leanne Hodson
  • Elina Ikonen
  • Hannele Yki-Järvinen

Research units

  • Minerva Foundation Institute for Medical Research Helsinki
  • University of Helsinki
  • University of Bonn
  • Cardiff University
  • National Institute for Health and Welfare
  • Lund University
  • University of Turku
  • Örebro University
  • University of Oxford

Abstract

The common patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant I148M predisposes to nonalcoholic liver disease but not its metabolic sequelae. We compared the handling of labeled polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFA) in vivo in humans and in cells harboring different PNPLA3 genotypes. In 148M homozygous individuals, triglycerides (TGs) in very low-density lipoproteins (VLDL) were depleted of PUFAs both under fasting and postprandial conditions compared with 148I homozygotes, and the PUFA/SFA ratio in VLDL-TGs was lower relative to the chylomicron precursor pool. In human PNPLA3-148M and PNPLA3-KO cells, PUFA but not SFA incorporation into TGs was increased at the expense of phosphatidylcholines, and under lipolytic conditions, PUFA-containing diacylglycerols (DAGs) accumulated compared with PNPLA3-148I cells. Polyunsaturated TGs were increased, while phosphatidylcholines (PCs) were decreased in the human liver in 148M homozygous individuals as compared with 148I homozygotes. We conclude that human PNPLA3-I148M is a loss-of-function allele that remodels liver TGs in a polyunsaturated direction by impairing hydrolysis/transacylation of PUFAs from DAGs to feed phosphatidylcholine synthesis.

Details

Original languageEnglish
Article numbere127902
JournalJCI Insight
Volume4
Issue number16
Publication statusPublished - 22 Aug 2019
MoE publication typeA1 Journal article-refereed

ID: 39086009